The Essential Role Of TRPM2in Ischemia-induced Neuronal Cell Death

Transient ischemia is a major cause leading to chronic impairment in memory and other brain functions. Post-ischemic generation of oxygen reactive species (ROS) and increase in the cytosolic Zn2+level ([Zn2+]c) are critical in delayed CA1pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2channel. Using in vivo bilateral common carotid artery occlusion (BCCAO) and in vitro oxygen-glucose deprivation (ODG) models, we found that genetic knockout of TRPM2strongly prohibited transient ischemia-induced delayed CA1pyramidal neuronal death and increase in the [Zn2+]c. Furthermore, time-elapse imaging of hippocampal cultured neurons showed that TRPM2deficiency specifically prevented cytosolic Zn2+accumulation during reperfusion without altering AMPA receptor-dependent Zn2+influx during ischemia. Consistent with the importance of ROS generation during reperfusion and ROS-induced TRPM2activation, H2O2-elicited increase in the [Zn2+]c was observed in WT hippocampal neurons but was completely absent in TRPM2-deficient neurons. Taken together, our results show a critical role for ROS-induced TRPM2activation during reperfusion in delayed increase in the [Zn+]c and CA1pyramidal neuronal death and identify TRPM2as a key signaling molecule in post-ischemic brain injury.